defining asthma: clinical criteria - columbia university€¦ · defining asthma: clinical criteria...

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Defining Asthma: Clinical Criteria

Asthma11%

n = 807

Recent wheeze20%

Atopy 34%

AHR 19%

From: Woolcock, AJ. “Asthma” in Textbook of Respiratory Medicine, 2nd ed.Murray, Nadel, eds.(Saunders:Philadelphia) pp. 1288-1330, 1994

Defining Asthma:Bronchial Hyperresponsiveness

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Impaired Ventilation in Asthma

Normal Asthmatic

From: Klarreich, Nature 424:873, 2003

Dynamic Imaging of Asthma

Pre-treatment Post-treatment

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Mucus Plugging is a Prominent Feature of Moderate to Severe Asthma

From: Bousquet et al., Am. J. Respir. Crit. Care Med., 161:1720, 2000

Some Landmarks in the History of the Immunology of Asthma*

*Highly biased view; therefore, commit to memory

1989: Early genetic mapping assigns chromosome 5q to the“cytokine gene cluster.”

Early 1990s: Asthma is an inflammatory disease.1990: Upregulation of ICAM-1 and LFA-1, adhesion

molecules, in a primate model of asthma1992: TH2 bias of lymphocytes in asthma1997: Experimental support grows for the “Hygiene hypothesis,”

first proposed in 1989.2000: Role of Tregs in regulation of asthma

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Nature of Inflammatory Cells inBiopsies From Airways of Asthmatics

From: Ollerenshaw and Woolcock., Am. Rev. Resp. Dis. 145:922, 1992

Defining Asthma: Pathological Features

Normal AsthmaticSmooth muscle

hypertrophy

Epithelialsloughing

Goblet cellhyperplasia

Subepithelialfibrosis

From: Bousquet et al., Am. J. Respir. Crit. Care Med., 161:1720, 2000

Inflammation

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Pro-survival and Metaplatic Pathwaysto Goblet Cell Production

QuickTime™ and aTIFF (Uncompressed) decompressor

are needed to see this picture.

From: Cohn, Am. J. Clin. Invest, 116:306, 2006

Tissue “Compartments” in Asthma



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Adhesion Molecules ICAM-1 and LFA-1 in Experimental Asthma

ICAM-1 LFA-1 Control

From: Wegner et al., Science 247:456, 1990

Asthma and the Immune Response

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Early- and Late-phase Allergic Reactions



Presence of Degranulated Eosinophils in Asthmatic Airways

From: Bousquet et al., N. Engl. J. Med. 323:1033, 1990

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Eosinophils and Asthma



From: Wills-Karp and Karp, Science 305:1726-1729, 2004

Asthma as a TH2-dominated Disease

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First Recognition of a TH2 Bias in Lymphocytes Obtained by BAL in Asthmatics

From: Robinson et al., New Engl. J. Med. 326:298,1992

Emergence of TH1 and TH2 Cellsfrom Naïve Precursors

From: Elias et al., J. Clin. Invest. 111:291, 2003

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STAT-6 Signaling PathwaysLeading to the Asthmatic Phenotype

From: Elias et al., J. Clin. Invest. 111:291, 2003



From: Wark and Gibson, Thorax 61:909, 2006

Defective Innate Immunity toRhinovirus Infection in Asthmatics

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Potential Drug Targets in Asthma



From: Barnes, Nature Reviews Drug Discovery 3:831,2004

Understanding the Immunology of AsthmaLeads to Insights Into Novel Therapeutics




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Who Gets Asthma?

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From: Shirakawa et al.,Science 275:77, 1997

From: Shirakawa et al., Science 275:77, 1997

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From: Shirakawa et al., Science 275:77, 1997

Environmental Influences and Asthma:The Hygiene Hypothesis

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Paradox: Why Does Chronic Infection with Helminths

Not Predispose to Allergy?

From: Yazdanbakhsh et al., Science 296:490, 2002

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An Alternative to the Hygiene Hypothesis: Regulatory T-cells

The Role of Regulatory T-cellsin Modifying TH2 Immunity

Modified from: Maizels & Yazdanbakhsh,Nature Rev. Immunol. 3:733, 2003

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Immunotherapy of Atopic Diseases: a Role for Tregs?



Following 2-year grass pollen immunotherapy (closed circles), there were significant increases in (A) allergen-stimulated PBMC production of IL-10; (B) serum concentrations of grass pollen allergen-specific IgG4; and (C) serum inhibitory activity for allergen-IgE binding to B cells compared with controls (open circles). These changes were accompanied by a reduction in symptoms and inhibition allergen-induced late cutaneous response.

From: Robinson et al., J. Clin. Invest 114:1389, 2004

Regulatory T-cells (Tregs) in Asthma



From: Robinson et al., J. Clin. Invest 114:1389, 2004

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Chemokines: the Gatekeepers ofInflammation

Chemokines Direct Traffic

From: Luster, Curr. Opin. Immunol. 14:129, 2002

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Chemokine Receptor Specificityin Th2 Cells and Eosinophils





Potential Drug Targets in Asthma:Chemokines and their Receptors




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Inflammatory Mediators asNovel Drug Targets

Lipid Mediators in Asthma:LTB4, PGD2, LTC4



From: Luster and Tager Nature Reviews Immunol. 4:711, 2004

LTC4S

PGD2LTB4

LTC4, LTD4

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Biological Activities of LTB4 and PGD2



From: Tilley and Boucher J. Clin. Invest. 115:13-16 (2005)

Adenosine Receptors as Drug Targets in Asthma

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Pro- and Anti-inflammatoryActivities of Adenosine in Asthma



From: Tilley and BoucherJ. Clin. Invest. 115:13-16 (2005)

Pharmacogenetics:The Future of Asthma Therapeutics?

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Summary of Genes Associated With Atopy

From: Halapi and Hakonarson,Curr. Opin. Pulm. Med. 10:22, 2003

Summary

1. Asthma is a chronic disease of the airways characterized by reversible airway obstruction, bronchial hyperreactivity, chronic inflammation, and mucus hypersecretion.

2. The allergic response is characterized by an early phase, dominated by degranulation of mast cells, followed by a late phase, involving T cells and eosinophils.

3. Asthma is accompanied by up-regulation of leukocyte adhesion molecules and the presence of multiple pro-inflammatory mediators, including chemokines, prostaglandins, leukotrienes, adenosine, and toxic products released from eosinophil granules.

4. Asthma is a prototypical Th2 disease, with increased production if IL-4 and IL-13, and STAT6 activation. The immunobiology of asthma is highly complex, but includes defects in the anti-viral response in airway epithelia.

5. The hygiene hypothesis states that asthma may arise from an imbalance in the Th1 and Th2 lymphocyte populations, possibly from differences in exposure to Th1-polarizing stimuli early in life.

6. An alternative view is that asthma arises from a defect in immune regulation. Insufficient production of Tregs may predispose to airway sensitization and atopy.

7. Future insights into the cellular immunology and genetics underlying asthma offer hope for future therapeutics.

defining asthma: clinical criteria - columbia university€¦ · defining asthma: clinical criteria...

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